Summary: Alzheimer?s disease (AD) is twice as prevalent in AA and 1.5 times in LA populations compared to Caucasians. Despite this, non-Caucasians are vastly under-represented in AD research including clinical trials and genetic studies. Further, there are no multi-omics studies to date in diverse populations. Based on the rationale that multi-omics studies can identify disease-relevant pathways and therapeutic targets, AMP-AD Target Discovery and Preclinical Validation Project was launched. This effort led to the generation and analysis of RNA- sequencing (RNAseq) based transcriptome, whole genome sequence (WGS), proteome, metabolome and epigenome data on >2,500 brain samples from Caucasian patients with AD and non-AD neuropathologies, as well as unaffected controls. This vast amount of data has been made available to the research community. These data have also been utilized to identify or validate potential risk mechanisms in AD and other neurodegenerative diseases and led to the data-driven identification and nomination of over 500 key driver genes/candidate targets for AD. Despite these advances for Caucasians, the multi-omic landscape of diverse AD, non-AD and control brains are unknown. Multi-omics profiling of diverse cohorts is essential for the discovery of the full spectrum of disease-relevant therapeutic targets that will be of utility to all populations affected with AD. In this supplement, we propose to generate and analyze RNAseq data from 3 brain regions of 331 AA or LA patients that represent the spectrum of AD and related disorders. The objective of this proposal is to identify pathways, molecules and potential therapeutic targets of AD in these diverse cohorts utilizing brain transcriptome and other existing data. Comparative studies will be conducted between findings from this proposal and those from the Caucasian cohorts within AMP-AD. These comparisons are expected to identify both shared and population-specific AD pathways and molecules and can ultimately inform the extent of utility for AD therapeutic targets across populations. The proposal is ?shovel-ready? with available samples and data. We will leverage existing infrastructure, protocols, analytic pipelines that we and others already established for large-scale multi-omics studies in AMP-AD. Thus, the proposed study is poised to successfully fill the knowledge gap for disease pathways and therapeutic targets of AD for minority populations. The specific aims are: 1) To generate a brain transcriptome map in diverse populations across the AD spectrum: We will perform brain RNAseq in 3 brain regions (993 brain samples) to generate a detailed brain transcriptome map in these diverse populations. 2) To identify molecular targets for AD in diverse populations: Using data from Aim 1, we will discover differentially expressed genes and networks in AD, their behavior across multiple brain regions and multiple pathologies and nominate a list of therapeutic targets. If funded, this study will enhance the target discovery potential of these diverse cohorts and establish the groundwork for these pioneering multi-omics studies in minority populations.